Protection levulinates

The coupling protocols described in the two previous examples can be combined to allow for the synthesis of branched carbohydrates.19 The automated solid-phase synthesis of a tetrasaccharide is illustrated in Scheme 4. Both glycosyl phosphate and glycosyl imidate building blocks were used along with acetate and levulinate esters as temporary protecting groups. 

Wong and co-workers developed an efficient orthogonal protection-deprotec-tion strategy aimed at the synthesis of pentasaccharide libraries based on the galactose derivative 349.1 [Scheme 4.M9].664 The levulinate ester, chloroacetate... 

There is a very large number of different ester protecting groups available and only the more common representatives in carbohydrate chemistry will be treated here. This includes acetate and substituted acetates such as chloroacetate, pivaloate, and levulinate groups. Aroyl groups are frequently used, such as benzoyl and substituted benzoyl e. g. p-phenylbenzoyl and 2,4,6-trimethylbenzoyl groups. 

The levulinoyl esters are prepared from the free hydroxyl group by treatment of levulinic acid with DCC [255,256] or l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDAC) [257] in the presence of DMAP (O Scheme 38). Additionally, 3 - and 5 -0-levulinyl protected derivatives of 2 -deoxy nucleosides have been prepared by regioselective enzymatic acylation using a variety of lipases and acetonoxime levulinate as acylating agent [258]. In contrast to other ester substituents, the 0-levulinoyl group is far less prone to migration [259]. 

A few examples of chemoselective additions of allyltitanium reagents to aliphatic and aromatic carbonyl compounds are reported in Table 7. Appreciable chemoselectivity toward the aldehydic function is achieved by the titanium ate conqtlex (23), whereas the reverse chemoselectivity toward ketones is realized using aminotitanium complex (104) and the analogous ate complexes (24) and (25), as is shown in Table 7. This is very interestii since it represents a rare case of chemoselectivity in favor of carbanion addition to ketones. A tentative explanation of this inverse chemoselection considers a fast transfer of the aminyl ligand onto the aldehyde function which becomes protected , as in (105), and thus unreactive in respect to the keto group. Ketones react also selectively compared with esters, as is shown by the reaction of ethyl levulinate (1) with the ate complex (23 equation 40). ... 

Candida antarctica Lipase, trifluoroethyl levulinate, THF, 40"C, 4 days, 65-83% yield. The method was used for the selective protection of the primary alcohol of the galactose saccharide. ... 

The route via methyl glycoside as the protected form and the final return to the hemiacetal by acid hydrolysis is only possible if the final product is stable under the necessary acidic conditions. Thus, if the substituents on the intermediate 3.36 were acetyl rather than benzyl, they would disappear partially during deprotection. Most sugars themselves are very stable in an acidic medium. However, fructose is partially transformed into levulinic acid (CH3COCH2CH2COOH) in an acidic medium at 100°C. As to deoxyribose, very mild acidic conditions suffice for its quantitative transformation into levulinic acid. The most frequent case is when acid removal of the protecting substituent... 

Levulinic esters. Alcohols can be protected as the levuhnates, readily prepared by reaction of the alcohol with the anhydride in pyridine at 25°. The protecting group can be removed by NaBH4, which selectively reduces carbonyl groups in the presence of ester groups. This reaction is usually quantitative. This... 

In order to selectively obtain the a-substituted condensation products from levulinate esters, it is necessary to protect the ketone group. Ethyl levulinate reacts with one mole of ethylene glycol to form the cyclic ketal. Condensation of the protected ester with benzaldehyde gave the a-benzylidene ester in 73% yield (Figure 3). 

Certain functionalised esters combine the virtues of acyl protection (ease of introduction, electronic deactivation, lability to base) with the ability to be deprotected under specialised conditions that leave other esters unaffected. Of these, the only example that has seen reasonably widespread application is the levulinate (Lev) derivative which, in chemistry that parallels the cleavage of ClAc derivatives with soft nucleophiles, are cleavable by conversion of the comparitively reactive ketone functionality into a nucleophilic entity that can cyclise onto the ester carbonyl releasing the protected hydroxyl. The example in Figure 2.45 shows that the acetates survive unscathed in Lev deprotection with hydrazine so that only the 2-OH is released [63]. 

As shown in Scheme 8.2, template 4 allowed preparation of carbamates at the C-3 position by selective removal of the levulinate protecting group followed by reaction with isocyanates. The three templates 5, 6, and 7 supported introduction of diversity at both the C-3 and C-2 positions by removal of the base-labile protecting group at C-2 and subsequent derivatizations to form antides (Scheme 8.3). Reduction of the C-3 azido group to a primary amine and reaction with isocyanates... 

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